The nuclear receptor superfamily constitutes a class of ligand- dependent transcriptional factors that regulate gene expression during many biological processes, including development, cellular proliferation and differentiation. The activity of these receptors is relevant to disease since alterations in receptor signaling pathways have been linked to various disease processes. Our laboratory has identified and cloned a novel nuclear orphan receptor named RTR. The objective of this study is to identify the biological functions of RTR. This includes identification of its target genes and to understand the mechanism by which RTR regulates gene expression. In addition, we like to determine its potential role in disease and the therapeutic potential of this signaling pathway. The expression pattern of this receptor during development and in the adult is limited. RTR is expressed in embryonic stem cells during neuronal cell differentiation, in trophoblast cells and in the testis. In embryonal carcinoma cells RTR is down-regulated when when cells are induced to differentiate. RTR acts as a repressor of transcription. For example, it can inhibit the transactivation by the nuclear receptor ERR1. We have demonstrated that the co-repressor N-COR can interact with RTR and likely mediates the repressor function of RTR. However, no interaction was observed between RTR and the co-repressor SMRT. Recently we cloned a novel gene referred to as RAP80 that is able to interact with RTR and may play a role in the repressor function of RTR. RAP80 is an 80 kD nuclear protein containing two zinc finger domains at its carboxy terminus. RAP80 is present in the nucleus in a speckled manner. It is expressed in many different cell types. Although N-COR and RAP80 are able to compete for binding to RTR, different regions of RTR are involved in the interaction. What domain of RAP80 is required for RTR interaction is being determined. - nuclear receptor, co-repressor, gene regulation, transcription, repression, orphan receptor,trophoblast, testis